Composition for treating atopy or pruritus comprising n-acetyl or n-acyl amino acid

ABSTRACT

The present disclosure relates to a composition for preventing, alleviating or treating pruritus and/or atopy using an N-acetylamino acid or an N-acylamino acid having almost no side effects on the human body. Also, the present disclosure relates to a cosmetic composition for moisturizing skin or soothing skin. The composition of the present disclosure may be utilized to ameliorate a problematic skin condition caused by various causes, or to safely and effectively alleviate or treat pruritus and/or atopy without concern about side effects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 17/668,678, filed on Feb. 10, 2022, which is adivisional application of U.S. patent application Ser. No. 16/766,891,filed on May 26, 2020, which is a § 371 national stage entry ofInternational Application No. PCT/KR2018/014483, filed on Nov. 23, 2018,which claims priority to Korean Patent Application No. 10-2018-0145159,filed on Nov. 22, 2018, and Korean Patent Application No.10-2017-0158599, filed on Nov. 24, 2017, the entire contents of whichare incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to a composition for preventing ortreating atopy, pruritus or atopy accompanied by pruritus, moisturizingskin or soothing skin, which contains an N-acetyl or N-acylamino acid asan active ingredient.

BACKGROUND ART

Pruritus (itch) is defined as an unpleasant sensation that causes thedesire to scratch or rub skin (Andersen H H et al., Human surrogatemodels of histaminergic and non-histaminergic itch, ActaDermato-Venereologica. 95 (7): 7717. (2015)). Although it is a symptomcommonly observed in skin diseases and systemic diseases, itscharacteristics are not fully known yet.

It is known that about 280 million people globally, 4% of the worldpopulation, have difficulty with pruritus, with higher incidence thanpsoriasis (2-3%) (Vos, T et al., Years lived with disability (YLDs) for1160 sequelae of 289 diseases and injuries 1990-2010: a systematicanalysis for the Global Burden of Disease Study 2010, Lancet. 380(9859): 216396. (2012)).

Pruritus can be induced or aggravated by various stimuli includingphysical, mechanical and chemical factors. In addition,inflammation-mediating substances induce pruritus in variousinflammatory skin diseases. However, not all types of pruritus areassociated with the mediating substances, and pruritus caused bymechanical stimulation, electrical stimulation or skin dryness may occurregardless of mediating substances.

According to the data of the Korean National Health Information Portal(http://health.mw.go.kr), histamine, serotonin, prostaglandin E,tachykinin, cytokines, proteases, opioid peptides, platelet-activatingfactor, etc. are known as pruritus-inducing mediating substances.

For treatment of pruritus, various therapies are available for now, suchas antihistamines, steroids, antibiotics, antiviral drugs, antifungalmedicines, anesthetics, probiotics, immunosuppressants, phototherapysuch as UV, etc., but the therapeutic effect is temporary or limiteddepending on the type of pruritus. In addition, adrenocorticotropichormones and corticosteroids can be used only in short term for acute orsevere cases due to side effects.

Atopic dermatitis is an eczema-like skin lesion occurring in people withatopic constitution. It is also called endogenous eczema or Besnier'spurigo. The cause is unknown but believed to involve genetics. It showsdistinct symptoms and progress distinguished from other common eczema ordermatitis. 70-80% of infantile eczema is due to atopic dermatitis. Thesymptoms vary with age and are usually classified into three stages. (1)Infancy (around 2 months to 3 years): Flare, exudation and desquamationoccur on the face, particularly on the cheeks, and the itch is verysevere. If the symptoms are aggravated, the same change occurs also onthe scalp together with scurf and flare and desquamation occur on theskin throughout the body. The whole skin turns rough and bluish white.The symptoms occur around 2-3 months after birth and heal well by oneyear of age, but can recur. In general, the symptoms are aggravated inwinter. (2) Childhood (around 4-10 years): Papules and purigo around 4-5years on the limbs (particularly on the front elbow and the back of theknee) and develop into lichenification. (3) Adolescence (12 years andolder): Lichenification occurs not only on the limbs but also on theface, chest, nape, etc. Pediatric asthma often occurs together, andfamily members tend to develop asthma or atopic dermatitis. Because thesymptoms last long and do not heal well, long-term patient treatment isnecessary. However, the symptoms are ameliorated with age. For severesymptoms, ointments (antihistamine, vitamin A or vitamin D) are used andantipruritics are used together (Doosan Encyclopedia,http://www.doopedia.co.kr/).

The cause of pruritus and atopic dermatitis is unclear in many casesand, despite the presence of various therapeutic agents includingsteroids, the therapeutic effect is only temporary or limited. Inaddition, the steroid drugs have side effect problems associated withmisuse or abuse.

Therefore, development of a new safe therapy which is effective forpruritus and/or atopic dermatitis caused by various causes is keenlyneeded.

The foregoing description of the background art is intended only to helpunderstanding of the background of the present disclosure and it shouldnot be construed as accepting that the background art is already wellknown to those of ordinary skill in the art.

DISCLOSURE Technical Problem

The inventors of the present disclosure have made efforts to find asubstance that can be safely prescribed for pruritus and/or atopicdermatitis caused by various causes with no concern about side effects.As a result, they have identified that an N-acetyl or N-acylamino acidis very effective for pruritus and/or atopy and have completed thepresent disclosure.

Accordingly, the present disclosure is directed to providing acomposition for preventing, improving or treating atopy.

The present disclosure is also directed to providing a composition forpreventing, improving or treating pruritus.

The present disclosure is also directed to providing a composition forpreventing, improving or treating atopy and pruritus.

The present disclosure is also directed to providing a composition formoisturizing skin or soothing skin.

Other objects and advantages of the present disclosure will be moreclearly understood from the following detailed description, claims anddrawings.

Technical Solution

In an aspect of the present disclosure, the present disclosure providesa composition for preventing, improving or treating atopy, whichcontains an N-acetylamino acid, an N-acylamino acid or a salt thereof asan active ingredient.

In another aspect of the present disclosure, the present disclosureprovides a composition for preventing, improving or treating pruritus,which contains an N-acetylamino acid, an N-acylamino acid or a saltthereof as an active ingredient.

In another aspect of the present disclosure, the present disclosureprovides a composition for preventing, improving or treating atopy andpruritus, which contains an N-acetylamino acid, an N-acylamino acid or asalt thereof as an active ingredient.

The inventors of the present disclosure have made efforts to find asubstance that can be safely prescribed for pruritus and/or atopicdermatitis caused by various causes with no concern about side effects.As a result, they have identified that an N-acetyl or N-acylamino acidis very effective for pruritus and/or atopy.

In the present disclosure, the term activity of preventing, improving ortreating “atopy” refers to the activity of preventing, improving ortreating atopic disease or atopic syndrome. The atopic disease or atopicsyndrome collectively refers to a disease or syndrome caused by allergicreactions whereby the human body becomes extremely sensitive uponcontact or without direct contact with an allergic antigen. Examplesinclude atopic allergy, atopic eczema, atopic dermatitis, allergicconjunctivitis, allergic rhinitis, asthma, etc., although not beinglimited thereto.

According to examples of the present disclosure, the composition of thepresent disclosure shows therapeutic effect for atopic dermatitis in anin-vivo experiment on an animal model of Balb/c mouse in which atopicdermatitis is induced with 2,4-dinitrofluorobenzene (DNFB) (Example 4),significantly decreases the level of immunoglobulin E (IgE) increased inatopic dermatitis (Example 5), and significantly decreases theexpression of interleukin-4 (IL-4) and interferon γ, which are TH2immunoregulatory cytokines associated with the lesion of atopicdermatitis (Example 6).

In the present disclosure, the term “pruritus” or “itch” is notspecially limited and is understood to include paroxysmal pruritus,winter pruritus, anal pruritus, vulvar pruritus, scrotal pruritus,aquagenic pruritus, scalp pruritus, nasal pruritus, neck itch, oralpruritus, ocular pruritus, cholestatic pruritus, pruritus accompanied byinternal diseases such as chronic renal failure, malignant tumor,iron-deficiency anemia, polycythemia vera, hyperthyroidism,hypothyroidism, diabetes, acquired immune deficiency syndrome, etc. andpruritus accompanied by systemic skin diseases such as lichen simplexchronicus, prurigo, trichotillomania, neurotic excoriation, skin-pickingbehavioral disorder, delusional parasitosis, etc.

Paroxysmal pruritus is paroxysmally occurring pruritus and is found inlichen simplex chronicus, dermatitis, etc.

Winter pruritus occurs in about 50% or more of people aged 70 years orolder and should be distinguished from pruritus caused by pruritic skindiseases or systemic diseases such as scabies, lichen planus, etc. Forwomen, it may occur as a symptom of postmenstrual syndrome. Skin drynessdue to decreased water content and gradually decreased sebum secretionin aged skin is the major cause and fine fissures and scaling occurmainly in the upper limbs and tibial regions.

Anal pruritus is the unpleasant sensation around the anus, causing thedesire to scratch, and is frequently associated with psychogenicfactors. It may occur regardless of age but occurs more frequently aftermiddle life. However, not all the causes of anal pruritus arepsychogenic, and contamination and irritation around the anus may be thecause. The irritation may be aggravated by colorectal and anal diseasessuch as anal fissure, hemorrhoids, anal fistula and chronic diarrhea,pungent food, medications, etc. Various infectious diseases byStaphylococcus, Streptococcus, molds, Candida, herpes simplex virus,etc. may induce pruritus. Among them, Candida infection is the commonestand causes fissures and sodden epidermis. Skin diseases around the anus,such as soriasis, seborrhoeic dermatitis, lichen planus, etc., may alsocause severe pruritus and lesions can be observed in other parts, too.Anal neurodermatitis is characterized by violent itching, at which timethe patient may tear at the affected area until bleeding is induced.Manifestations may be identical to lichen simplex chronicus elsewhere onthe body.

Candida infection is the most frequent cause of vulvar pruritus. Othercauses may include trichomonas vaginitis or contact dermatitis caused bypads, contraceptive devices, vaginal wash, condoms, etc. After middlelife, lichen sclerosus et atrophicus is the commonest cause. Severepruritus may occur also in Fox-Fordyce disease. However, temporaryvulvar pruritus may also be caused by abrasion, sweating, vulvarcongestion during pregnancy, etc.

Regarding scrotal pruritus, the scrota of adults are immune to fungalinfection like the scalp but lichen simplex chronicus occurs frequentlythere. The cause may be psychogenic in many cases. Severelichenification may occur and the symptoms can last a few years despiteintensive treatment.

Aquagenic pruritus is characterized by the development of severe,unpleasant, pricking-like itching evoked by contact with water occurringwithin several minutes after the contact or even after the contact hasbeen discontinued. It is irrelevant to the temperature of water and nospecial change is observed on the skin. In some patients, it can occurdue to the change in ambient temperature. About ⅓ of patients showfamily history. It is usually chronic and does not respond well totreatment. Although increased histamine level is observed on skin and inblood, the symptoms are not ameliorated by antihistamines. Hence, it isthought that histamine is not the only cause. Distinction is necessarybecause the symptoms are similar to those of polycythemia vera.

Scalp pruritus can occur independently without distinct lesions on thescalp. It occurs in middle-aged and elderly people, but the cause is notknown well. The itchiness is very severe, occurs paroxysmally, and isaggravated by fatigue or stress. It needs to be distinguished fromherpetic dermatitis, lichen simplex chronicus, seborrhoic dermatitis,psoriasis, etc.

Patients with biliary hepatocirrhosis suffer from severe systemicpruritus. The pruritus is associated with increased level of bile acidin blood plasma. Application of bile acid at a concentration clinicallyinducing pruritus directly onto blistery skin lesions may induce severepruritus.

Pruritus occurs in about 20-50% of chronic renal failure patientsreceiving hemodialysis treatment. The pruritus occurs topically orsystemically. The symptoms become severe mostly during hemodialysis, butthe hemodialysis may temporarily alleviate the symptoms. It is reportedthat there is no direct relationship between the concentration ofhistamine, urea and creatinine in blood and the severity of pruritus.Although some patients show skin dryness, most have normal skin and theuse of moisturizers does not alleviate or relieve the symptom.

If systemic pruritus occurs in middle or old ages without specialreason, extensive examination of malignant tumor is necessary. Pruritusoccurs consistently in 15-25% of patients with Hodgkin's disease (arepresentative example of lymphoma). Sometimes burning pain and flushingsensation are accompanied, although the cause is not known. Systemicpruritus can occur also in leukemia.

Iron deficiency may also be the cause of pruritus. It is reported thatoral administration of iron supplements to patients with polycythemiavera and iron deficiency decreased pruritus.

About 50% of patients with polycythemia vera experience severe prurituswithin several minutes after exposure to water, which lasts for about15-60 minutes. It is called bath itch since it usually occurs aftertaking a bath. No special change is observed on the skin and it occursirrespective of the water temperature. But, increased histamine level isobserved in serum and urine. It is though that platelet aggregation isthe cause inducing several pruritus-mediating substances includinghistamine.

Severe systemic pruritus can occur in hyperthyroidism. Increasedcutaneous blood flow increases the skin surface temperature and lowersthe itch threshold. In hypothyroidism, systemic pruritus may occur dueto severe skin dryness caused by myxoedema. In both diseases, pruritusmay occur around the genital areas due to mucocutaneous candidiasis.

In some diabetic patients, pruritus may occur around the genital areasdue to mucocutaneous candidiasis. However, systemic pruritus may occurin other patients.

Pruritus is one of the major symptoms of acquired immune deficiencysyndrome. The cause of pruritus in patients with acquired immunedeficiency syndrome includes scabies, pediculosis, candidiasis,seborrhoic dermatitis and systemic diseases such as renal failure,cholestasis, etc. In addition, systemic papule or pigmented rash causingcharacteristically severe pruritus often occurs.

Lichen simplex chronicus is a disease characterized by repeated rubbingor scratching of the skin, causing thick, leathery skin. Lichen simplexchronicus may occur secondarily in normal skin as a result of repeatedpruritus. In general, it is more common in 30s to 50s and is seen moreoften in women compared to men.

Prurigo is a disease characterized by multiple nodules and severepruritus. It is not cured well and tends to last for a long time. Itscause is not known well and anemia, liver disease, HIV, pregnancy, renalfailure, mental stress, etc. may be the cause.

Trichotillomania is a mental disorder characterized by an abnormal urgethat results in the pulling out of one's hair. Mental and socialstresses are the cause. Stress in family or school lives, siblingrivalry, move, hospitalization of parents, mother-daughter relationship,etc. may be the cause. It occurs in nearly all age groups from childrento adults.

Neurotic excoriation is a disease characterized by the repeated andcompulsive urge to pick and gouge one's own skin, often leading to skinlesions. Patients admit that their behavior is responsible for thelesions but cannot resist it. It can occur at any age but occurs morefrequently in middle-aged women. It often occurs due to mental stress.It often occurs on skin lesion areas such as pruritus, insect sting,etc. Neurotic excoriation also correlates with depression,obsessive-compulsive disorder and anxiety. This symptom occurs morefrequently in people with obsessive, stubborn, supervisorycharacteristics and perfectionism tendencies with fear for failure.

Factitious dermatitis is a dermatitis occurring from intentionalself-inflicted skin damage in an attempt to attract sympathy or avoidresponsibility. Skin lesions are produced mechanically or by chemicals,corrosives, etc. In addition, nails, sharp instruments, hot metals, etc.are used too. The patient harms himself/herself in order to satisfypsychological needs. It occurs more frequently in women and can occur inall age groups. Most patients are childish and dependent and haveimpulse control disorders.

Skin-picking behavioral disorder is an obsessive self-inflictingbehavior repeated for a long time. The self-inflicting behavior oftenleads to a suicidal attempt and, in adolescence, it may be attempted toshow off bravery.

Delusional parasitosis is a delusional disorder in which patientsincorrectly believe they are infested with parasites. It is a chronic,monosymptomatic hypochondriasis without damage to personality orthinking ability. Patients provide pieces of skin, lint, tissue paper,tape, etc. and ask for parasite examination. It is reported that 2-3% ofthe patients have experienced parasitic infection before.

In addition, there are nasal pruritus accompanied by nasal diseases suchas rhinitis, ocular pruritus accompanied by ocular diseases such asconjunctivitis, and oral pruritus accompanied by dental diseases.

According to an example of the present disclosure, the composition ofthe present disclosure showed a remarkable effect of suppressingpruritus in an in-vivo experiment on an animal model of Balb/c mouse inwhich pruritus is induced with 2,4-dinitrofluorobenzene (DNFB) (Example8).

In a specific exemplary embodiment of the present disclosure, thecomposition of the present disclosure is used for preventing, improvingor treating atopy accompanied by pruritus.

TSLP (thymic stromal lymphopoietin) is known to play an important rolein the maturation of T cells through activation of antigen-presentingcells, and is also known to cause TH2 inflammatory responses by inducingCD11c+ myeloid dendritic cells (Ziegler S F et al., Thymic stromallymphopoietin in normal and pathogenic T cell development and function.Nat Immunol 2006; 7: 709-14). It is known that the TSLP is increased inthe lesions of atopy patients and is associated with the severity ofatopic dermatitis (Sano Y et al., Thymic stromal lymphopoietinexpression is increased in the horny layer of patients with atopicdermatitis. Clin Exp Immunol 2013; 171: 330-7).

Unlike other inflammatory diseases, atopic dermatitis is characterizedin that it is accompanied by pruritus. It was identified that, inaddition to the correlation to the severity of atopic dermatitis, theTSLP is the cause of pruritus in atopic dermatitis (Wilson S R et al.,The epithelial cell-derived atopic dermatitis cytokine TSLP activatesneurons to induce itch. Cell. 2013; 155(2): 285-95).

Accordingly, the composition of the present disclosure may beeffectively used in prevention, improvement or treatment of atopyaccompanied by pruritus.

In a specific exemplary embodiment of the present disclosure, theN-acetylamino acid is one or more amino acid selected from a groupconsisting of N-acetylalanine, N-acetylthreonine, N-acetylarginine andN-acetyltryptophan.

In a specific exemplary embodiment of the present disclosure, theN-acetylamino acid is one or more amino acid selected from a groupconsisting of N-acetyl-L-alanine, N-acetyl-L-threonine,N-acetyl-L-arginine and N-acetyl-L-tryptophan.

In a specific exemplary embodiment of the present disclosure, theN-acylamino acid is N-acyltryptophan or N-acylalanine.

In a specific exemplary embodiment of the present disclosure, theN-acylamino acid is N-acyl-L-tryptophan or N-acyl-L-alanine.

In the present disclosure, the term “acyl” or “acyl group” refers to aradical having the general formula RCO, derived by the removal of ahydroxyl (OH) group from a carboxylic acid, without special limitation.R may be one or more of any substituent that can be bonded to CO,without limitation. Particularly, if R is an aromatic radical, the groupis called “aroyl”, which is also an acyl group. Examples of the acylgroup include formyl (HCO—), acetyl (CH₃CO—), propionyl (C₂H₅CO—),butyryl (C₃H₇CO—), valeryl (C₄H₉CO—), pentanoyl (CH₃(CH₂)₃CO—),palmitoyl (C₁₅H₃₁CO—), stearoyl (C₁₇H₃₃CO—), oleoyl (C₁₇H₃₁CO—), oxalyl(—CO—CO—), malonyl (—COCH₂CO—), succinyl (—CO(CH₂)2CO—), benzoyl(C₆H₅CO—), toluoyl (CH₃—C₆H₄—CO—), salicyloyl (HO—C₆H₄—CO—), cinnamoyl(C₆H₅CH═CHCO—), naphthoyl (C₁₀H₇CO—), phthaloyl (CO—C₆H₄—CO—), furoyl

undecanoyl (CH₃(CH₂)₉CO—) and docosenoyl with an OH group removed fromdocosenoic acid, although not being limited thereto.

Specifically, the N-acyl-L-tryptophan is one or more amino acid selectedfrom a group consisting of N-propionyl-L-tryptophan,N-butyryl-L-tryptophan, N-pentanoyl-L-tryptophan,N-undecanoyl-L-tryptophan, N-palmitoyl-L-tryptophan,N-(Z)-docos-13-enoyl-L-tryptophan, N-stearyl-L-tryptophan andN-oleoyl-L-tryptophan, although not being limited thereto.

Specifically, the N-acyl-L-alanine is N-acetyl-γ-glutammyl-L-alanine orN-palmitoyl-L-alanine, although not being limited thereto.

In the present disclosure, the term “containing as an active ingredient”refers to an amount sufficient to achieve the effect or activity of theN-acetyl or N-acylamino acid. In a specific exemplary embodiment of thepresent disclosure, the N-acetyl or N-acylamino acid is contained in thecomposition of the present disclosure in an amount of, for example,0.001 mg/kg or more, specifically 0.1 mg/kg or more, more specifically 1mg/kg or more, further more specifically 10 mg/kg or more. Because theN-acetyl or N-acylamino acid has few side effects on the human body evenwhen administered in excess amounts, the upper limit of the amount ofthe N-acetyl or N-acylamino acid contained in the composition of thepresent disclosure may be adequately determined by those skilled in theart.

It is understood that the N-acetyl or N-acylamino acid, which iscontained in the composition of the present disclosure as an activeingredient, includes, not only the compound itself, but also itspharmaceutically, sitologically or cosmetically acceptable salt,hydrate, solvate or prodrug.

In the present disclosure, the term “pharmaceutically acceptable salt”,“sitologically acceptable salt” or “cosmetically acceptable salt” refersto salt of the compound which does not negatively affect the biologicalactivity and physical properties of the compound and does not inducesevere stimulation in an organism to which the compound is administered.The pharmaceutically, sitologically or cosmetically acceptable salt maybe obtained by reacting the compound of the present disclosure with aninorganic acid such as, hydrochloric acid, bromic acid, sulfuric acid,nitric acid, phosphoric acid, etc., a sulfonic acid such asmethnesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.,or an organic acid such as tartaric acid, formic acid, citric acid,acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid,isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconicacid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylicacid, etc. In addition, the salt may be obtained by reacting thecompound of the present disclosure with a base to form an ammonium salt,an alkali metal salt such as a sodium or potassium salt, etc., analkaline earth metal salt such as a calcium or magnesium salt, a slatwith an organic base such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, etc., or an amino acid salt witharginine, lysine, etc., although not being limited thereto.

The term, “pharmaceutically acceptable hydrate”, “sitologicallyacceptable hydrate” or “cosmetically acceptable hydrate” refers to ahydrate of the N-acetyl or N-acylamino acid which exert the desiredpharmacological effect. The term “pharmaceutically acceptable solvate”,“sitologically acceptable solvate” or “cosmetically acceptable solvate”refers to a solvate of the N-acetyl or N-acylamino acid compound whichexert the desired pharmacological effect. The hydrate and the solvatemay also be prepared by using the above-descried acids, and they arealso included in the pharmaceutically, sitologically or cosmeticallyacceptable salt in a broad sense.

The term “pharmaceutically acceptable prodrug”, “sitologicallyacceptable prodrug” or “cosmetically acceptable prodrug” refers to aderivative of the N-acetyl or N-acylamino acid which has to undergobioconversion prior to exhibiting the pharmacological effect of theN-acetyl or N-acylamino acid. The prodrug is prepared to improvechemical stability, patient compliance, bioavailability or organselectivity, to improve convenience of preparation, to prolong theduration of action, or to reduce side effects. The prodrug of thepresent disclosure may be prepared easily using the N-acetyl orN-acylamino acid according to a method commonly employed in the art(e.g., Burger's Medicinal Chemistry and Drug Chemistry, 5th ed., 1:172-178 and 949-982 (1995)).

In a specific exemplary embodiment of the present disclosure, thecomposition of the present disclosure is a pharmaceutical composition.

A pharmaceutically acceptable carrier contained in the pharmaceuticalcomposition of the present disclosure may be one commonly used in theart and may include lactose, dextrose, sucrose, sorbitol, mannitol,starch, gum acacia, calcium phosphate, alginate, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc., althoughnot being limited thereto. The pharmaceutical composition of the presentdisclosure may further contain, in addition to these ingredients, alubricant, a wetting agent, a sweetener, a flavor, an emulsifier, asuspending agent, a preservative, etc. Suitable pharmaceuticallyacceptable carriers and formulations are described in detail inRemington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present disclosure may beadministered orally or parenterally. The parenteral administration canbe made nasally, ocularly, intravenously, subcutaneously,intramuscularly, intraperitoneally, transdermally, etc.

An adequate administration dosage of the pharmaceutical composition ofthe present disclosure may vary depending on such factors as formulationmethod, administration method, the age, body weight and sex of apatient, pathological condition, diet, administration time,administration route, excretion rate and responsiveness. An ordinarilyskilled physician can easily determine and prescribe an administrationdosage which is effective for the desired treatment or prevention. In aspecific exemplary embodiment of the present disclosure, a dailyadministration dosage of the pharmaceutical composition of the presentdisclosure is 0.001-100 mg/kg.

The pharmaceutical composition of the present disclosure may beformulated as a unit dosage form or in a multiple-dosage receptacle byusing a pharmaceutically acceptable carrier and/or excipient accordingto a method that can be easily carried out by those of ordinary skill inthe art to which the present disclosure belongs. The formulation may bein the form of a solution in an oily or aqueous medium, a suspension, anemulsion, an extract, a powder, a granule, a tablet or a capsule and mayfurther contain a dispersant or a stabilizer.

The pharmaceutical composition of the present disclosure may also beprepared into a formulation for external application to skin, anaerosol, a spray, an eye drop, an oral medication or an injection.

The pharmaceutical composition of the present disclosure may be used forhuman or animals.

In a specific exemplary embodiment of the present disclosure, thecomposition of the present disclosure is a food composition.

The food composition according to the present disclosure may be used asa functional food or may be added to various foods. The foods to whichthe composition of the present disclosure can be added include, forexample, beverages, alcohol beverages, confectionery, diet bar, dairyproducts, meat, chocolate, pizza, bakery, ramen, other noodles, gums,ice creams, multivitamin supplements, health food supplements, etc.

The food composition of the present disclosure may contain, in additionto the N-acetyl or N-acylamino acid as the active ingredient, aningredient commonly added during preparation of food, for example, aprotein, a carbohydrate, a fat, a nutrient, a seasoning agent or aflavoring agent. Examples of the carbohydrate are common sugars such asmonosaccharides, e.g., glucose, fructose, etc., disaccharides, e.g.,maltose, sucrose, oligosaccharides, etc., and polysaccharides, e.g.,dextrin, cyclodextrin, etc.; and sugar alcohols such as xylitol,sorbitol, erythritol, etc. As the flavoring agent, a natural flavor(thaumatin or stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.))or a synthetic flavor (saccharin, aspartame, etc.) may be used. Forexample, when the food composition of the present disclosure is preparedas a drink or a beverage, it may further contain, in addition to theN-acetyl or N-acylamino acid, citric acid, fructose syrup, sucrose,glucose, acetic acid, malic acid, fruit juice, various plant extracts,etc.

The present disclosure provides a functional health food as a foodcomposition containing an N-acetyl or N-acylamino acid or asitologically acceptable salt as an active ingredient. The functionalhealth food refers to a food prepared by adding the N-acetyl orN-acylamino acid to a foodstuff such as a drink, a tea, a spice, a gum,confectionery, etc. or preparing into a capsule, a powder, a suspension,etc. to provide special health effect. Unlike general medicines, it isadvantageous in that there is no side effect that may occur duringlong-term use of medicines. The functional health food of the presentdisclosure is very useful because it can be ingested routinely. Thecontent of the N-acetyl or N-acylamino acid in functional health foodmay vary depending on the type of the functional health food within arange not negatively affecting the inherent taste of the food. Usually,its content in the food is 0.01-50 wt %, specifically 0.1-20 wt %. And,when the functional health food is in the form of a pill, a granule, atablet or a capsule, it may be added in an amount of usually 0.1-100 wt%, specifically 0.5-80 wt %. In a specific exemplary embodiment, thefunctional health food of the present disclosure may be in the form of apill, a tablet, a capsule or a drink.

The food composition of the present disclosure may be used as a food forhuman, a feed for animals, a feed additive, etc.

In a specific exemplary embodiment of the present disclosure, thecomposition of the present disclosure is a cosmetic composition.

In another aspect of the present disclosure, the present disclosureprovides a cosmetic composition for moisturizing skin or soothing skin,which contains an N-acetylamino acid, an N-acylamino acid or acosmetically acceptable salt as an active ingredient.

In a specific exemplary embodiment of the present disclosure, thecosmetic composition of the present disclosure improves one or more skincondition selected from a group consisting of skin dryness, edema,erythema, inflammation, eschar, abrasion and lichenification.

When the composition of the present disclosure is prepared as a cosmeticcomposition, the composition of the present disclosure may furthercontain, in addition to the N-acetyl or N-acylamino acid, an ingredientcommonly used in a cosmetic composition, for example, a commonly usedadjuvant such as an antioxidant, a stabilizer, a solubilizer, a vitamin,a pigment and a flavor, and a carrier. Besides, the composition of thepresent disclosure may further contain, in addition to the N-acetyl orN-acylamino acid, an atopy-improving agent, a pruritus-improving agent,or an agent for moisturizing or soothing skin which has been usedhitherto within a range not negatively affecting the (atopy and/orpruritus-improving) action of the active ingredient.

As the carrier, purified water, a monohydric alcohol (ethanol or propylalcohol), a polyhydric alcohol (glycerol, 1,3-butylene glycol orpropylene glycol), a higher fatty acid (palmitic acid or linoleic acid),an oil or fat (wheat germ oil, camellia oil, jojoba oil, olive oil,squalene, sunflower oil, macadamia nut oil, avocado oil, hydrogenatedsoybean lecithin or fatty acid glyceride), etc. may be used, althoughnot being limited thereto. If necessary, a surfactant, a sterilizer, anantioxidant, a UV absorber, an anti-inflammatory agent or a coolingagent may be further added.

The surfactant may be selected from a group consisting ofpolyoxyethylene, hydrogenated castor oil, polyoxyethylene oleyl ether,polyoxyethylene monooleate, polyoxyethylene glyceryl monostearate,sorbitan monostearate, sorbitan, sucrose fatty acid ester, hexaglycerylmonolaurate, polyoxyethylene-reduced lanolin, POE, glycerylpyroglutamate, isostearic acid diester, N-acetylglutamine and isostearylester.

The sterilizer may be selected from a group consisting of hinokitiol,triclosan, chlorhexidine gluconate, phenoxyethanol, resorcin,isopropylmethylphenol, azulene, salicylic acid and zinc pyrithione.

As the antioxidant, any of butylhydroxyanisole, gallic acid, propylgallate and erythorbic acid may be used.

As the UV absorber, any of a benzophenone such as dihydroxybenzophenone,etc., melanin, ethyl p-aminobenzoate, p-dimethylaminobenzoic acid2-ethylhexyl ester, cinoxate, p-methoxycinnamic acid 2-ethylhexyl ester,2-(2-hydroxy-5-methylphenyl)benzotriazole, urocanic acid and fine metaloxide particle may be used.

As the anti-inflammatory agent, dipotassium glycyrrhetinate or allantoinmay be used. And, as the cooling agent, capsicum tincture or 1-mentholmay be used.

The composition may be prepared into any formulation in which theN-acetyl or N-acylamino acid can be mixed as an active ingredient.Examples of the cosmetic formulation for improving atopy or pruritusinclude a tonic, a shampoo, a rinse, a hair conditioner, a hair spray, apowder, a gel, a cream, an essence, a lotion, a sol-gel, an emulsion, anoil, a wax, a spray, a mist, etc., although not being limited thereto.In addition, it may be prepared as a mask pack containing the N-acetylor N-acylamino acid.

Advantageous Effects

The features and advantages of the present disclosure may be summarizedas follows:

(i) The present disclosure provides a composition for preventing,improving or treating atopy by using an N-acetyl or N-acylamino acid,which has few side effects on the human body.

(ii) In addition, the present disclosure provides a composition forpreventing, improving or treating pruritus by using an N-acetyl orN-acylamino acid.

(iii) The composition of the present disclosure may be usefully used toimprove or treat pruritus and/or atopic dermatitis caused by variouscauses safely and effectively without the concern of side effects.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A shows a process of inducing atopic dermatitis-like skin lesionsby repeatedly applying 2,4-dinitrofluorobenzene (DNFB) to Balb/c mouseand administering a drug.

FIG. 1B shows a process of inducing atopic dermatitis lesions byrepeatedly applying 2,4-dinitrofluorobenzene (DNFB) to Nc/Nga mouse andadministering a drug.

FIG. 2A shows a result of applying 20 N-acetyl-L-amino acids on thedermatitis-induced area of atopic dermatitis-induced Balb/c mouse andthen measuring clinical skin scores (SCORAD) (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)-treated group).

FIG. 2B shows the images of the back skin of Balb/c mouse treated with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis and thentreated for 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 29.

FIG. 3A shows a result of applying N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on the dermatitis-induced area of atopicdermatitis-induced Nc/Nga mouse and then measuring clinical skin scores(SCORAD) (*P<0.05 versus 2,4-dinitrofluorobenzene (DNFB)-treated group).

FIG. 3B shows the images of the back skin of Nc/Nga mouse treated with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis and thentreated for 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 22.

FIG. 3C shows a result of treating Nc/Nga mouse with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis, treatingfor 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 22, and then staining the back skin tissuesliced to a thickness of 5 μm with hematoxylin/eosin.

FIG. 4A shows a result of treating Balb/c mouse with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis, treatingfor 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 29, and then measuring the total IgE levelin the serum sample of the mouse by ELISA (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)).

FIG. 4B shows a result of treating Nc/Nga mouse with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis, treatingfor 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 29, and then measuring the total IgE levelin the serum sample of the mouse by ELISA (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)).

FIG. 5A shows a result of treating Balb/c mouse with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis, treatingfor 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 29, and then measuring the quantity of IL4and interferon γ mRNAs in the skin tissue of the mouse (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)).

FIG. 5B shows a result of treating Nc/Nga mouse with2,4-dinitrofluorobenzene (DNFB) to induce atopic dermatitis, treatingfor 7 days with a control substance, N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-threonine, N-acetyl-L-arginine orN-acetyl-L-tryptophan on day 29, and then measuring the quantity of IL4and interferon γ mRNAs in the skin tissue of the mouse (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)).

FIG. 6 shows a result of comparing the atopic dermatitis-relievingeffect of L-form N-acetylalanine and N-acetyltryptophan with D/L-formand D-form N-acetylalanine and N-acetyltryptophan at a concentration of0.1% in Nc/Nga mouse in which atopic dermatitis is induced with DNFB(*P<0.05 versus 2,4-dinitrofluorobenzene (DNFB)).

FIG. 7 shows a result of comparing the pruritus-relieving effect ofL-form N-acetylalanine, N-acetylthreonine, N-acetylarginine andN-acetyltryptophan with D/L-form and D-form N-acetylalanine andN-acetyltryptophan at a concentration of 0.1% in Nc/Nga mouse in whichatopic dermatitis is induced with DNFB (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)).

FIG. 8 shows a result of applying N-acyl-L-tryptophan,N-acetyl-γ-glutammylalanine and N-palmitoyl-L-alanine onto thedermatitis-induced area of atopic dermatitis-induced Nc/Nga mouse andthen measuring clinical skin score (SCORAD) (*P<0.05 versus2,4-dinitrofluorobenzene (DNFB)-treated group).

FIG. 9 shows MS data of compound N-Acetyl-γ-glutammylalanine wassynthesized by Genescript (USA).

BEST MODE FOR CARRYING OUT INVENTION

Hereinafter, the present disclosure will be described in detail throughexamples. However, the following examples are for illustrative purposesonly and it will be obvious to those of ordinary skill in the art thatthe scope of the present disclosure is not limited by the examples.

EXAMPLES <Example 1> Test Animals and Reagents

7-week-old male Balb/c mice and 7-week-old male Nc/Nga mice werepurchased from Orient Bio (Seongnam, Gyeonggi-do, Korea) and maintainedunder specific pathogen-free conditions. The mice were housed in anair-conditioned animal room at a temperature of 25±1° C. and a relativehumidity of 40±5%, and they were given distilled water and laboratorydiet. Animal treatment and maintenance complied with the Principles ofLaboratory Animal Care (NIH Publication No. 85-23, revised in 1985) andthe guidelines of the Institutional Animal Care and Use Committee of theJeonbuk National University (KHUASP (SE)-15-021). All procedures wereconducted in accordance with the guidelines of the United StatesNational Institute of Health (NIH).

<Example 2> Induction of Atopic Dermatitis

In order to induce atopy-like dermatitis in Balb/c mice, DNFBsensitization was induced by applying 100 μL of 0.35%2,4-dinitrofluorobenzene (DNFB) (Sigma, USA) in acetone/olive oil (3:1)on the shaved back skin of the mice. Then, dermatitis was induced byapplying 100 μL of 0.25% DNFB on days 6, 9, 12, 15, 18 21, 24 and 27 onthe shaved back skin. Control mice were treated with a vehicle of thesame volume (FIG. 1A).

In order to establish a model more similar to an atopy model than thatof the Balb/c mice, atopy was induced in Nc/Nga mouse mice.Specifically, after inducing DNFB sensitization by applying 100 μL of0.35% 2,4-dinitrofluorobenzene (DNFB) in acetone/olive oil (3:1) on theshaved back skin, dermatitis was induced by applying 100 μL of 0.15%DNFB for 4-20 days, every other day. Control mice were treated with avehicle of the same volume (FIG. 1B).

<Example 3> Drug Treatment

After dissolving an N-acetyl or N-acylamino acid in phosphate-bufferedsaline to 0.1%, 200 μL of the solution was applied on the back skin ofthe mice every day, from day 22 until day 28 for the Balb/c atopicdermatitis model, and from day 15 until day 21 for the Nc/Nga atopicdermatitis model. When the N-acetyl or N-acylamino acid was treatedtogether with DNFB, they were treated with 12-hour intervals in order toavoid direct reaction between the DNFB and the N-acetyl or N-acylaminoacid. A non-treated group and a 2,4-dinitrofluorobenzene (DNFB) groupwere treated with phosphate-buffered saline of the same volume (FIGS.1A-1B). As the N-acetylamino acid, products purchased from Sigma-Aldrich(USA), MP scientific (USA), TCI (Tokyo Chemical Industry, Japan),Santacruz (USA), etc. were used without purification.

<Example 4> Evaluation of Skin-Soothing Effect and Severity of AtopicDermatitis

The degree of skin soothing and the severity of atopic dermatitis wereevaluated macroscopically according to the previously established SCORAD(SCORing Atopic Dermatitis) method (Oranje et al., 2007). The degree ofsymptoms such as edema, erythema, eschar, dryness, abrasion,lichenification, etc. was graded from 0 to 3 (0, no symptom; 1, mild; 2,moderate; 3, severe). The overall dermatitis score was determined fromthe sum of all individual scores (Table 1). The assessment was performedby an investigator who was blind to the grouping of the mice. As seenfrom Table 1, from among the 20 N-acetyl-L-amino acids,N-acetyl-L-cysteine, N-acetyl-L-alanine, N-acetyl-L-arginine,N-acetyl-L-threonine and N-acetyl-L-tryptophan showed significantskin-soothing and atopic dermatitis-treating effects.

TABLE 1 Mouse 1 Mouse 2 Ery- Ede- Es- Dry- Abra- Licheni- Ery- Ede- Es-Dry- Abra- Licheni- thema ma char ness sion fication Sum thema ma charness sion fication Sum Control 0 0 0 0 0 0 0 0 0 0 0 0 0 0 DNF 3 2 2 3 23 15 2 3 2 2 3 3 15 B (D) D + 2 2 2 2 2 3 13 2 1 2 3 2 3 13 N-acetyl-L-cysteine D + 1 1 1 2 1 0 6 1 1 1 0 1 0 4 N-acetyl-L- alanine D + 3 2 2 33 2 15 2 2 2 3 2 3 14 N-acetyl-L- asparagine D + 3 2 1 3 2 2 13 3 2 2 32 3 15 N-acetyl-L- phenyl- alanine D + 3 2 2 2 2 2 13 3 2 2 3 2 12 14N-acetyl-L- aspartic acid D + 1 1 1 2 1 1 7 1 1 1 0 1 1 5 N-acetyl-L-threonine D + 3 2 2 3 2 2 14 3 2 2 3 2 3 15 N-acetyl-L- leucine D + 3 22 2 2 2 13 3 2 2 3 2 3 15 N-acetyl-L- serine D + 3 2 1 3 2 2 13 2 3 2 32 2 14 N-acetyl-L- proline D + 1 1 1 0 1 1 5 0 1 1 1 0 0 3 N-acetyl-L-tryptophan D + 3 2 3 3 1 3 15 2 2 2 3 2 3 14 N-acetyl-L isoleucine D + 32 2 2 2 3 14 2 2 2 3 2 2 13 N-acetyl-L- glutamic acid D + 3 2 2 2 2 3 143 2 2 3 2 3 15 N-acetyl-L- glycine D + 3 2 2 2 2 3 14 2 2 2 2 2 3 13N-acetyl-L- valine D + 1 1 1 1 1 1 6 1 1 1 1 1 1 6 N-acetyl-L- arginineD + 3 2 2 3 2 1 13 3 3 2 2 2 3 15 N-acetyl-L- Lysine D + 3 2 3 3 2 2 153 2 2 3 2 3 15 N-acetyl-L- tyrosine D + 2 2 2 2 2 3 13 2 2 2 2 2 2 12N-acetyl-L- glutamine D + 3 2 2 3 2 3 15 3 2 2 3 2 3 15 N-acetyl-L-histidine D + 2 2 2 3 2 3 14 3 2 3 3 2 3 16 N-acetyl-L- methionine Mouse3 Ery- Ede- Es- Dry- Abra- Licheni- Devia- thema ma char ness sionfication Sum Mean tion Control 0 0 0 0 0 0 0 DNF 3 3 2 2 3 3 16 15.330.58 B (D) D + 1 2 2 2 2 2 11 12.33 1.15 N-acetyl-L- cysteine D + 1 1 10 1 1 5 5 1 N-acetyl-L- alanine D + 3 3 3 3 2 2 16 15 1 N-acetyl-L-asparagine D + 3 2 2 3 1 3 14 14 1 N-acetyl-L- phenyl- alanine D + 3 2 22 2 1 12 13 1 N-acetyl-L- aspartic acid D + 1 1 2 1 0 1 6 6 1N-acetyl-L- threonine D + 3 2 2 3 2 1 13 14 1 N-acetyl-L- leucine D + 32 2 3 2 2 14 14 1 N-acetyl-L- serine D + 3 2 2 3 1 2 13 13.33 0.59N-acetyl-L- proline D + 0 0 2 0 2 0 4 4 1 N-acetyl-L- tryptophan D + 3 22 3 1 3 14 14.33 0.58 N-acetyl-L isoleucine D + 1 2 2 3 2 2 12 13 1N-acetyl-L- glutamic acid D + 3 2 2 3 2 3 15 14.67 0.58 N-acetyl-L-glycine D + 2 2 2 3 1 2 12 13 1 N-acetyl-L- valine D + 1 1 1 1 0 1 55.67 0.58 N-acetyl-L- arginine D + 3 2 2 3 2 2 14 14 1 N-acetyl-L-Lysine D + 3 2 2 2 2 2 13 14.33 1.15 N-acetyl-L- tyrosine D + 2 2 2 2 21 11 12 1 N-acetyl-L- glutamine D + 3 2 2 13 2 2 14 14.67 0.58N-acetyl-L- histidine D + 2 2 2 3 2 3 14 14.67 1.15 N-acetyl-L-methionine

Also, as seen from FIG. 2A, from among the 20 N-acetyl-L-amino acids,N-acetyl-L-cysteine, N-acetyl-L-alanine, N-acetyl-L-arginine,N-acetyl-L-threonine and N-acetyl-L-tryptophan showed significant atopicdermatitis-treating effect in the Balb/c atopic dermatitis model (FIG.2A). The apparent degree of dermatitis was also decreased remarkably inthe atopy-induced mice treated with N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-threonine orN-acetyl-L-tryptophan (FIG. 2B).

As seen from FIG. 3 , from among the N-acetyl-L-cysteine,N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-threonine andN-acetyl-L-tryptophan, which exhibited effects in the Balb/c atopicdermatitis model, N-acetyl-L-alanine and N-acetyltryptophan showedatopic dermatitis-treating effect in the atopic dermatitis model ofNc/Nga mice (FIG. 3A). Nc/Nga mice are widely used as an atopicdermatitis model. In particular, N-acetyl-L-alanine andN-acetyltryptophan showed remarkable effect in this model (FIG. 3B).After extracting back skin tissues of the atopic dermatitis-induced anddrug-treated Nc/Nga mice of Example 2, the tissues were fixed with anAccustain formalin-free fixative solution and then prepared intoparaffin blocks. The paraffin blocks were sliced to a thickness of 5 μmand the change in the thickness of the epidermal and dermal layers wasobserved by staining with hematoxylin/eosin. The thickness of theepidermal and dermal layers, which was increased by the induction ofatopic dermatitis, was significantly decreased by the treatment withN-acetyl-L-alanine or N-acetyl-L-tryptophan (FIG. 3C).

<Example 5> Measurement of Serum IgE Level

After treatment with the test substance, the mice were sacrificed andblood was taken from the heart. After isolating serum from the blood,IgE level was measured. Specifically, after attaching antibodies dilutedin a buffer solution onto a 96-well plate and incubating overnight at 4°C., experiment was conducted using an IgE ELISA kit (BD Biosciences, SanDiego, Calif.) according to the provided manual. The quantity of the IgEprotein was determined by measuring absorbance at 450 nm using amicroplate reader. As seen from FIGS. 4A-4B, the treatment of theatopy-induced Balb/c mice with N-acetyl-L-cysteine, N-acetyl-L-alanine,N-acetyl-L-arginine, N-acetyl-L-threonine and N-acetyl-L-tryptophanresulted in significant decrease in serum IgE level (FIG. 4A), and thetreatment of the atopy-induced Nc/Nga mice with N-acetyl-L-alanine andN-acetyl-L-tryptophan resulted in significant decrease in serum IgElevel (FIG. 4B). Because the serum IgE level is indicative of theseverity of atopic dermatitis, the result of FIGS. 4A-4B shows thatN-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-threonine andN-acetyl-L-tryptophan have atopic dermatitis-treating effect.

<Example 6> Measurement of IL4 and Interferon y by QuantitativeReal-Time PCR

After isolating total RNA from the atopy-induced skin tissue using 500μL of Trizol (Life Technologies, USA) according to the manufacturer'sprotocol and synthesizing cDNA using the Superscript III reversetranscriptase (Life Technologies, USA), real-time PCR was conducted byreacting with the primers of IL4 and interferon γ to be analyzed. Thereal-time PCR was conducted on a StepOne Plus PCR cycler (AppliedBiosystems) using SYBR Green (Applied Biosystems, Foster City, Calif.).The mRNA expression data were analyzed by the ΔΔCT method and werenormalized to β-actin for gene detection. The primers necessary for thereal-time PCR were purchased from Qiagen (USA). As seen from FIGS.5A-5B, the treatment of the atopy-induced Balb/c mice withN-acetyl-L-cysteine, N-acetyl-L-alanine, N-acetyl-L-arginine,N-acetyl-L-threonine and N-acetyl-L-tryptophan significantly decreasedthe level of IL4 and interferon γ in the skin tissue (FIG. 5A), and thetreatment of the atopy-induced Nc/Nga mice with N-acetyl-L-alanine andN-acetyl-L-tryptophan significantly decreased the level of IL4 andinterferon γ in the skin tissue. IL4 is known to induce TH2 response andinterferon γ is known to induce TH1 response. Accordingly, the result ofFIGS. 5A-5B shows that N-acetyl-L-alanine, N-acetyl-L-arginine,N-acetyl-L-threonine and N-acetyl-L-tryptophan exhibit therapeuticeffects by inhibiting TH2 and TH1 responses activated by atopicdermatitis.

<Example 7> Stereo-Specificity of N-Acetylamino Acid

In order to investigate the effect of L-form, L/D-form and D-formN-acetylalanine and N-acetyltryptophan on atopic dermatitis, theirdermatitis-treating effect was evaluated for the atopic dermatitis modelof Nc/Nga mice. As a result, the L/D-form and D-form N-acetylalanine andN-acetyltryptophan had no effect and only the L-form showed remarkableeffect (FIG. 6 ). This shows that the pruritus-inhibiting action bythese substances is stereo-specific.

<Example 8> Pruritus Inhibition Test

In order to investigate whether L-form, L/D-form and D-formN-acetylalanine, N-acetylarginine, N-acetylthreonine andN-acetyltryptophan inhibit pruritus caused by atopic contact dermatitis,20 μL of 0.1% 2,4-dinitrofluorobenzene (DNFB) solution and 0.1%N-acetylamino acid dissolved in physiological saline were applied onceonto the right ear 10 minutes after the final treatment (day 27) with2,4-dinitrofluorobenzene (DNFB) (Physiological saline was applied to anegative control group), and then pruritus was measured for 1 hour. FIG.7 compares the pruritus-relieving effect of L-form N-acetylalanine,N-acetylthreonine, N-acetylarginine and N-acetyltryptophan with D/L-formand D-form N-acetylalanine and N-acetyltryptophan at 0.1% after theinduction of pruritus with DNFB. The L-form N-acetylalanine,N-acetylthreonine, N-acetylarginine and N-acetyltryptophan significantlyinhibited pruritus, whereas the D/L-form and D-form N-acetylalanine andN-acetyltryptophan had little effect. This result shows that thepruritus-inhibiting action by these substances is stereo-specific.

<Example 9> Synthesis of Acyl Derivatives of Tryptophan

In order to evaluate the effect of N-acyltryptophan compounds other thanN-acetyltryptophan, N-propionyltryptophan, N-butryltryptophan,N-pentanoyltryptophan, N-undecanoyltryptophan, N-palmitoyltryptophan,N-(Z)-docos-13-enoyltryptophan and N-stearoyltryptophan,N-oleoyltryptophan were synthesized according to the reaction schemedescribed below. The reagents used in this example were purchased fromSigma-Aldrich (USA), TCI (Japan), Alfa Aesar (USA), Acros (USA), Hanawa(Japan), etc. and used without purification. The purity of thesynthesized compounds and the progress of reaction were identified bythin layer chromatography (TLC) using the PLC Silica gel 60 F254, 0.5 mm(Merck). The substances separated by TLC were identified using UV lamps(254 nm, 365 nm). Separation was conducted by medium-pressure liquidchromatography (MPLC) using a silica gel column cartridge (4-120 g,RediSep Rf) and PLC2020 (Gilson) or by high-performance liquidchromatography (HPLC) using an Agilent 5 Prep-C18 100×21.2 mm column, aYL9100 Semi-prep HPLC system (YL9101 S vacuum degasser, YL9111 S binarypump, YL9120S UV/Vis detector; Young Lin Instrument). Mass analysis ofthe products was conducted with Agilent 6130 Quadrupole LC/MS. The NMRspectra for structural analysis of the products were measured with aBruker ultra-shield 300 MHz NMR spectrometer and a Bruker ultra-shield500 MHz NMR Spectrometer. Chloroform-d and dimethylsulfoxide-d₆(Cambridge Isotope Laboratories) were used as NMR solvents andtetramethylsilane (TMS) was used as an internal standard. The NMR datawere presented in ppm units.

<Example 9-1> Preparation of N-Propionyltryptophan

First, for preparation of methylpropionyl L-tryptophanate, a mixture ofpropionic acid (2.36 mmol), L-tryptophan methyl ester hydrochloride(2.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60mmol), hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8mmol) dissolved in dichloromethane was stirred at room temperature for12 hours. The reaction mixture was concentrated, diluted with asaturated NaHCO₃ solution, and then extracted 3 times with ethylacetate. The extracted organic solvent layer was combined, washed withbrine, washed with 1 N HCl, and then washed again with brine. Theorganic solvent layer was dried on anhydrous MgSO₄, concentrated andthen purified by medium-pressure liquid chromatography (MPLC) usingn-hexane and ethyl acetate. The yield was 74% and the characteristics ofthe methylpropionyl L-tryptophanate are as follows. ¹HNMR (500 MHz,chloroform-d) δ 8.19 (s, 1H), 7.61-7.53 (m, 1H), 7.39 (dt, J=8.2, 0.9Hz, 1H), 7.22 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.16-7.07 (m, 1H), 7.00 (d,J=2.4 Hz, 1H), 6.04-5.88 (m, 1H), 5.00 (dt, J=7.9, 5.3 Hz, 1H), 3.73 (s,3H), 3.44-3.29 (m, 2H), 2.21 (qd, J=7.6, 1.2 Hz, 2H), 1.14 (t, J=7.6 Hz,3H). LC-MS (ESI), calcd for C₁₅H₁₈N₂O₃ 274.1, found m/z 275.1 (M+H⁺).

In order to prepare N-propionyltryptophan from themethylpropionyl-L-tryptophanate, a NaOH (1.48 mmol) solution was addedto the methylpropionyl-L-tryptophanate (0.37 mmol) dissolved intetrahydrofuran and the mixture was stirred at room temperature for 12hours. After adding water, the reaction mixture was extracted withdichloromethane. The aqueous layer was adjusted to pH 1 by adding 1 NHCl and then extracted 3 times with ethyl acetate. The extracted organicsolvent layer was dried on anhydrous MgSO₄ and then concentrated. Theyield was 92% and the characteristics of the N-propionyltryptophan areas follows. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (d, J=2.4 Hz, 1H), 8.03(d, J=7.9 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.35-7.27 (m, 1H), 7.13 (d,J=2.3 Hz, 1H), 7.06 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 6.98 (ddd, J=8.0,6.9, 1.1 Hz, 1H), 4.46 (d, J=4.8 Hz, 1H), 3.15 (d, J=5.0 Hz, 1H), 3.01(d, J=8.8 Hz, 1H), 2.08 (qd, J=7.5, 3.1 Hz, 2H), 0.94 (d, J=7.6 Hz, 3H).LC-MS (ESI), calcd for C₁₄H₁₆N₂O₃ 260.1, found m/z 261.1 (M+H⁺).

<Example 9-2> Preparation of N-Butyryltryptophan

First, for preparation of methylbutyryl L-tryptophanate, butyric acid(2.36 mmol), a mixture of L-tryptophan methyl ester hydrochloride (2.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60 mmol),hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8 mmol)dissolved in dichloromethane was stirred at room temperature for 12hours. The reaction mixture was concentrated, diluted with a saturatedNaHCO₃ solution, and then extracted 3 times with ethyl acetate. Theextracted organic solvent layer was combined, washed with brine, washedwith 1 N HCl, and then washed again with brine. The organic solventlayer was dried on anhydrous MgSO₄, concentrated, and then purified bymedium-pressure liquid chromatography (MPLC) using n-hexane and ethylacetate. The yield was 83% and the characteristics of the methylbutyrylL-tryptophanate are as follows. ¹H NMR (500 MHz, chloroform-d) δ 8.15(s, 1H), 7.61-7.51 (m, 1H), 7.39 (dt, J=8.1, 0.9 Hz, 1H), 7.22 (ddd,J=8.1, 7.0, 1.1 Hz, 1H), 7.15 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.01 (d,J=2.4 Hz, 1H), 5.98 (d, J=7.9 Hz, 1H), 5.01 (dt, J=7.9, 5.3 Hz, 1H),3.73 (s, 3H), 3.39-3.29 (m, 2H), 2.16 (t, J=7.5 Hz, 2H), 1.70-1.58 (m,3H), 0.93 (t, J=7.4 Hz, 3H). LC-MS (ESI), calcd for C₁₆H₂₀N₂O₃ 288.2,found m/z 289.2 (M+H⁺).

In order to prepare N-butyryltryptophan from the methylbutyrylL-tryptophanate, a NaOH (1.48 mmol) solution was added to themethylbutyryl L-tryptophanate (0.37 mmol) dissolved in tetrahydrofuranand the mixture was stirred at room temperature for 12 hours. Afteradding water, the reaction mixture was extracted with dichloromethane.The aqueous layer was adjusted to pH 1 by adding 1 N HCl and thenextracted 3 times with ethyl acetate. The extracted organic solventlayer was dried on anhydrous MgSO₄ and then concentrated. The yield was94% and the characteristics of the N-butyryltryptophan are as follows.¹H NMR (500 MHz, chloroform-d) δ 8.30 (s, 1H), 7.60 (d, J=8.1 Hz, 1H),7.38 (dt, J=8.2, 0.9 Hz, 1H), 7.22 (ddd, J=8.1, 7.0, 1.2 Hz, 1H), 7.14(ddd, J=8.0, 7.1, 1.0 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.08 (d, J=7.6Hz, 1H), 4.95 (dd, J=7.6, 5.4 Hz, 1H), 3.44-3.32 (m, 2H), 2.11-2.08 (m,2H), 1.58 (q, J=7.4 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H). LC-MS (ESI), calcdfor C₁₅H₁₈N₂O₃ 274.1, found m/z 275.1 (M+H⁺).

<Example 9-3> Preparation of N-Pentanoyltryptophan

First, for preparation of methylpentanoyl L-tryptophanate, a mixture ofpentanoic acid (2.36 mmol), L-tryptophan methyl ester hydrochloride(2.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60mmol), hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8mmol) dissolved in dichloromethane was stirred at room temperature for12 hours. The reaction mixture was concentrated, diluted with asaturated NaHCO₃ solution, and then extracted 3 times with ethylacetate. The extracted organic solvent layer was combined, washed withbrine, washed with 1 N HCl, and then washed again with brine. Theorganic solvent layer was dried on anhydrous MgSO₄, concentrated, andthen purified by medium-pressure liquid chromatography (MPLC) usingn-hexane and ethyl acetate. The yield was 85% and the characteristics ofthe methylpentanoyl L-tryptophanate are as follows. ¹H NMR (500 MHz,chloroform-d) δ 8.14 (s, 1H), 7.56 (dt, J=8.0, 1.0 Hz, 1H), 7.39 (dd,J=8.1, 0.9 Hz, 1H), 7.22 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.15 (ddd,J=8.0, 7.1, 1.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 5.97 (d, J=8.0 Hz, 1H),5.00 (dt, J=7.9, 5.4 Hz, 1H), 3.46-3.23 (m, 2H), 2.32-2.09 (m, 2H),1.61-1.54 (m, 2H), 1.51-1.19 (m, 2H), 0.90 (t, J=7.3 Hz, 3H). LC-MS(ESI), calcd for C₁₇H₂₂N₂O₃ 302.2, found m/z 303.2 (M+H⁺).

In order to prepare N-pentanoyltryptophan from the methylpentanoylL-tryptophanate, a NaOH (1.48 mmol) solution was added to themethylpentanoyl L-tryptophanate (0.37 mmol) dissolved in tetrahydrofuranand the mixture was stirred at room temperature for 12 hours. Afteradding water, the reaction mixture was extracted with dichloromethane.The aqueous layer was adjusted to pH 1 by adding 1 N HCl and thenextracted 3 times with ethyl acetate. The extracted organic solventlayer was dried on anhydrous MgSO₄ and then concentrated. The yield was90% and the characteristics of the N-pentanoyltryptophan are as follows.¹H NMR (500 MHz, chloroform-d) δ 8.29 (s, 1H), 7.62-7.51 (m, 1H),7.44-7.32 (m, 1H), 7.22 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.14 (ddd, J=8.0,7.0, 1.0 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 4.99(dt, J=7.7, 5.4 Hz, 1H), 3.44-3.30 (m, 2H), 2.18-2.13 (m, 2H), 1.54 (p,J=7.6 Hz, 2H), 1.28 (dt, J=9.0, 7.2 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H).LC-MS (ESI), calcd for C₁₆H₂₀N₂O₃ 288.2, found m/z 289.2 (M+H⁺).

<Example 9-4> Preparation of N-undecanoyltryptophan

First, for preparation of methylundecanoyl L-tryptophanate, a mixture ofundecanoic acid (2.36 mmol), L-tryptophan methyl ester hydrochloride(2.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60mmol), hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8mmol) dissolved in dichloromethane was stirred at room temperature for12 hours. The reaction mixture was concentrated, diluted with asaturated NaHCO₃ solution and then extracted 3 times with ethyl acetate.The extracted organic solvent layer was combined, washed with brine,washed with 1 N HCl, and then washed again with brine. The organicsolvent layer was dried on anhydrous MgSO₄, concentrated, and thenpurified by medium-pressure liquid chromatography (MPLC) using n-hexaneand ethyl acetate. The yield was 91% and the characteristics of themethylundecanoyl L-tryptophanate are as follows. ¹H NMR (500 MHz,chloroform-d) δ 8.12 (s, 1H), 7.61-7.52 (m, 1H), 7.39 (dt, J=8.1, 0.9Hz, 1H), 7.25-7.21 (m, 1H), 7.22-7.12 (m, 1H), 7.01 (d, J=2.4 Hz, 1H),5.97 (d, J=7.9 Hz, 1H), 5.88-5.78 (m, 1H), 3.73 (s, 3H), 3.43-3.27 (m,2H), 2.23-2.14 (m, 3H), 2.11-2.01 (m, 2H), 1.60 (s, 5H), 1.38 (q, J=7.0Hz, 2H), 1.28 (d, J=2.1 Hz, 9H). LC-MS (ESI), calcd for C₂₃H₃₄N₂O₃386.2, found m/z 387.2 (M+H⁺).

In order to prepare N-undecanoyltryptophan from the methylundecanoylL-tryptophanate, a NaOH (1.48 mmol) solution was added to themethylundecanoyl L-tryptophanate (0.37 mmol) dissolved intetrahydrofuran and the mixture was stirred at room temperature for 12hours. After adding water, the reaction mixture was extracted withdichloromethane. The aqueous layer was adjusted to pH 1 by adding 1 NHCl and then extracted 3 times with ethyl acetate. The extracted organicsolvent layer was dried on anhydrous MgSO₄ and then concentrated. Theyield was 88% and the characteristics of the N-undecanoyltryptophan areas follows. ¹H NMR (500 MHz, chloroform-d) δ 8.30-8.27 (m, 1H), 7.60 (d,J=7.9 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.25-7.20 (m, 1H), 7.18-7.11 (m,1H), 7.05 (d, J=2.3 Hz, 1H), 6.06 (d, J=7.5 Hz, 1H), 5.91-5.75 (m, 1H),5.06-4.96 (m, 2H), 3.44-3.30 (m, 2H), 2.16-2.11 (m, 2H), 2.05 (q, J=7.2Hz, 2H), 1.54 (d, J=7.3 Hz, 2H), 1.41-1.36 (m, 2H), 1.30-1.22 (m, 11H).LC-MS (ESI), calcd for C₂₂H₃₂N₂O₃ 372.2, found m/z 373.2 (M+H⁺).

<Example 9-5> Preparation of N-Palmitoyltryptophan

First, for preparation of methylpalmitoyl L-tryptophanate, a mixture ofpalmitoic acid (2.36 mmol), L-tryptophan methyl ester hydrochloride(2.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60mmol), hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8mmol) dissolved in dichloromethane was stirred at room temperature for12 hours. The reaction mixture was concentrated, diluted with asaturated NaHCO₃ solution and then extracted 3 times with ethyl acetate.The extracted organic solvent layer was combined, washed with brine,washed with 1 N HCl, and then washed again with brine. The organicsolvent layer was dried on anhydrous MgSO₄, concentrated and thenpurified by medium-pressure liquid chromatography (MPLC) using n-hexaneand ethyl acetate. The yield was 84% and the characteristics of themethylpalmitoyl L-tryptophanate are as follows. ¹H NMR (500 MHz,chloroform-d) δ 8.11 (s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.51-7.33 (m, 1H),7.19-7.06 (m, 1H), 7.01 (d, J=2.4 Hz, 1H), 5.99 (d, J=8.0 Hz, 1H), 5.00(dt, J=8.0, 5.3 Hz, 1H), 3.73 (s, 3H), 3.39-3.29 (m, 2H), 2.38 (d, J=7.5Hz, 2H), 2.19-2.15 (m, 2H), 1.67 (d, J=7.3 Hz, 2H), 0.91 (s, 3H). LC-MS(ESI), calcd for C₂₈H₄₄N₂O₃ 456.2, found m/z 457.2 (M+H⁺).

In order to prepare N-palmitoyltryptophan from the methylpalmitoylL-tryptophanate, a NaOH (1.48 mmol) solution was added to themethylpalmitoyl L-tryptophanate (0.37 mmol) dissolved in tetrahydrofuranand the mixture was stirred at room temperature for 12 hours. Afteradding water, the reaction mixture was extracted with dichloromethane.The aqueous layer was adjusted to pH 1 by adding 1 N HCl and thenextracted 3 times with ethyl acetate. The extracted organic solventlayer was dried on anhydrous MgSO₄ and then concentrated. The yield was89% and the characteristics of the N-palmitoyltryptophan are as follows.¹H NMR (500 MHz, chloroform-d) δ 8.19 (s, 1H), 7.60 (d, J=7.9 Hz, 1H),7.40 (d, J=8.1 Hz, 1H), 7.27-7.21 (m, 1H), 7.18-7.12 (m, 1H), 7.08 (d,J=2.3 Hz, 1H), 4.99 (dd, J=9.2, 3.8 Hz, 1H), 3.44-3.34 (m, 2H), 2.38 (d,J=7.5 Hz, 2H), 2.14 (d, J=11.8 Hz, 2H), 1.65 (d, J=7.4 Hz, 2H), 1.28 (m,24H), 0.91 (s, 3H). LC-MS (ESI), calcd for C₂₇H₄₂N₂O₃ 442.2, found m/z443.2 (M+H⁺).

<Example 9-6> Preparation of N-(Z)-Docos-13-Enoyl-L-Tryptophan

First, for preparation of methyl-(Z)-docos-13-enoyl L-tryptophanate, amixture of (Z)-docos-13-enoic acid (2.36 mmol), L-tryptophan methylester hydrochloride (2.60 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60 mmol),hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8 mmol)dissolved in dichloromethane was stirred at room temperature for 12hours. The reaction mixture was concentrated, diluted with a saturatedNaHCO₃ solution, and then extracted 3 times with ethyl acetate. Theextracted organic solvent layer was combined, washed with brine, washedwith 1 N HCl, and then washed again with brine. The organic solventlayer was dried on anhydrous MgSO₄, concentrated, and then purified bymedium-pressure liquid chromatography (MPLC) using n-hexane and ethylacetate. The yield was 74% and the characteristics of themethyl-(Z)-docos-13-enoyl L-tryptophanate are as follows. ¹H NMR (500MHz, chloroform-d) δ 8.16 (s, 1H), 7.56 (dd, J=8.0, 1.1 Hz, 1H), 7.39(dt, J=8.2, 0.9 Hz, 1H), 7.22 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.14 (ddd,J=7.9, 7.0, 1.0 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 5.98 (d, J=7.9 Hz, 1H),5.43-5.31 (m, 2H), 5.00 (dt, J=7.9, 5.3 Hz, 1H), 3.72 (s, 3H), 3.39-3.29(m, 2H), 2.20-2.13 (m, 2H), 2.04 (q, J=6.7 Hz, 4H), 1.61 (q, J=10.0, 7.5Hz, 2H), 1.35-1.24 (m, 28H), 0.91 (t, J=6.9 Hz, 3H). LC-MS (ESI), calcdfor C₃₄H₅₄N₂O₃ 53/.4, found m/z 539.4 (M+H⁺).

In order to prepare N-(Z)-docos-13-enoyltryptophan from themethyl-(Z)-docos-13-enoyl L-tryptophanate, a NaOH (1.48 mmol) solutionwas added to the methyl-(Z)-docos-13-enoyl L-tryptophanate (0.37 mmol)dissolved in tetrahydrofuran and the mixture was stirred at roomtemperature for 12 hours. After adding water, the reaction mixture wasextracted with dichloromethane. The aqueous layer was adjusted to pH 1by adding 1 N HCl and then extracted 3 times with ethyl acetate. Theextracted organic solvent layer was dried on anhydrous MgSO₄ and thenconcentrated. The yield was 92% and the characteristics of theN-(Z)-docos-13-enoyltryptophan are as follows. ¹H NMR (500 MHz,chloroform-d) δ 8.24 (s, 1H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.42-7.37(m, 1H), 7.19-7.11 (m, 1H), 7.07 (d, J=2.4 Hz, 1H), 5.38 (td, J=4.4, 2.1Hz, 2H), 4.95 (dt, J=7.5, 5.5 Hz, 1H), 3.44-3.33 (m, 2H), 2.14 (dd,J=8.6, 6.8 Hz, 2H), 2.09-1.97 (m, 4H), 1.55 (t, J=7.4 Hz, 2H), 1.28 (dd,J=19.4, 13.4 Hz, 30H), 0.90 (t, J=6.9 Hz, 3H). LC-MS (ESI), calcd forC₃₃H₅₂N₂O₃ 524.4, found m/z 525.4 (M+H⁺).

<Example 9-7> Preparation of N-Stearoyl-L-Tryptophan

First, for preparation of methylstearoyl L-tryptophanate, a mixture ofstearoic acid (2.36 mmol), L-tryptophan methyl ester hydrochloride (2.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60 mmol),hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8 mmol)dissolved in dichloromethane was stirred at room temperature for 12hours. The reaction mixture was concentrated, diluted with a saturatedNaHCO₃ solution, and then extracted 3 times with ethyl acetate. Theextracted organic solvent layer was combined, washed with brine, washedwith 1 N HCl, and then washed again with brine. The organic solventlayer was dried on anhydrous MgSO₄, concentrated, and then purified bymedium-pressure liquid chromatography (MPLC) using n-hexane and ethylacetate. The yield was 80% and the characteristics of the methylstearoylL-tryptophanate are as follows. ¹H NMR (500 MHz, chloroform-d) δ 8.09(d, J=15.2 Hz, 1H), 7.56 (dd, J=7.9, 1.0 Hz, 1H), 7.39 (dt, J=8.2, 0.9Hz, 1H), 7.22 (ddd, J=8.1, 7.0, 1.2 Hz, 1H), 7.14 (ddd, J=7.9, 7.0, 1.0Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 5.00 (dt, J=7.9, 5.3 Hz, 1H), 3.73 (s,3H), 3.39-3.28 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.19-2.11 (m, 2H), 1.66(t, J=7.4 Hz, 2H), 1.59 (t, J=7.4 Hz, 2H), 0.91 (s, 3H). LC-MS (ESI),calcd for C₃₀H₄₈N₂O₃ 484.4, found m/z 485.4 (M+H⁺).

In order to prepare N-stearoyltryptophan from the methylstearoylL-tryptophanate, a NaOH (1.48 mmol) solution was added to themethylstearoyl L-tryptophanate (0.37 mmol) dissolved in tetrahydrofuranand the mixture was stirred at room temperature for 12 hours.

After adding water, the reaction mixture was extracted withdichloromethane. The aqueous layer was adjusted to pH 1 by adding 1 NHCl and then extracted 3 times with ethyl acetate. The extracted organicsolvent layer was dried on anhydrous MgSO₄ and then concentrated. Theyield was 84% and the characteristics of the N-stearoyltryptophan are asfollows. ¹H NMR (500 MHz, chloroform-d) δ 8.27-8.17 (m, 1H), 7.60 (d,J=7.9 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.15 (t,J=7.5 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.01 (d, J=7.5 Hz, 1H), 4.98 (dt,J=7.5, 5.5 Hz, 1H), 3.46-3.34 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.17-2.12(m, 2H), 1.68-1.63 (m, 2H), 1.56 (t, J=7.4 Hz, 2H), 1.29 (s, 24H), 0.91(s, 3H). LC-MS (ESI), calcd for C₂₉H₄₆N₂O₂ 470.4, found m/z471.4 (M+H⁺).

<Example 9-8> Preparation of N-Oleoyl-L-Tryptophan

First, for preparation of methyloleoyl L-tryptophanate, a mixture ofoleoic acid (2.36 mmol), L-tryptophan methyl ester hydrochloride (2.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2.60 mmol),hydroxybenzotriazole (HOBt) (2.60 mmol) and triethylamine (11.8 mmol)dissolved in dichloromethane was stirred at room temperature for 12hours. The reaction mixture was concentrated, diluted with a saturatedNaHCO₃ solution, and then extracted 3 times with ethyl acetate. Theextracted organic solvent layer was combined, washed with brine, washedwith 1 N HCl, and then washed again with brine. The organic solventlayer was dried on anhydrous MgSO₄, concentrated, and then purified bymedium-pressure liquid chromatography (MPLC) using n-hexane and ethylacetate. The yield was 73% and the characteristics of the methyloleoylL-tryptophanate are as follows. ¹H NMR (500 MHz, chloroform-d) δ 8.18(s, 1H), 7.56 (dd, J=7.9, 1.0 Hz, 1H), 7.39 (dt, J=8.1, 0.9 Hz, 1H),7.29 (s, 1H), 7.22 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 7.14 (ddd, J=8.0, 7.0,1.0 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 5.99 (d, J=7.9 Hz, 1H), 5.37 (qd,J=4.1, 2.1 Hz, 2H), 5.00 (dt, J=8.0, 5.3 Hz, 1H), 3.72 (s, 3H),3.39-3.28 (m, 2H), 2.20-2.13 (m, 2H), 2.08-1.99 (m, 5H), 1.60 (t, J=7.4Hz, 2H), 1.34-1.28 (m, 24H), 0.92-0.89 (m, 3H). LC-MS (ESI), calcd forC₃₀H₄₆N₂O₃ 482.4, found m/z 483.4 (M+H⁺).

In order to prepare N-oleoyltryptophan from the methyloleoylL-tryptophanate, a NaOH (1.48 mmol) solution was added to themethyloleoyl L-tryptophanate (0.37 mmol) dissolved in tetrahydrofuranand the mixture was stirred at room temperature for 12 hours. Afteradding water, the reaction mixture was extracted with dichloromethane.The aqueous layer was adjusted to pH 1 by adding 1 N HCl and thenextracted 3 times with ethyl acetate. The extracted organic solventlayer was dried on anhydrous MgSO₄ and then concentrated. The yield was86% and the characteristics of the N-oleoyltryptophan are as follows. ¹HNMR (500 MHz, chloroform-d) δ 8.22 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.40(dt, J=8.1, 0.9 Hz, 1H), 7.23 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 7.15 (ddd,J=8.0, 7.1, 1.0 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 5.37 (qd, J=5.3, 4.6,2.3 Hz, 2H), 4.95 (dt, J=7.3, 5.6 Hz, 1H), 3.45-3.33 (m, 2H), 2.17-2.10(m, 2H), 1.59-1.51 (m, 2H), 1.38-1.26 (m, 26H), 0.91 (d, J=6.8 Hz, 3H).C₂₉H₄₄N₂O₂ 468.3, found m/z 469.3 (M+H⁺).

<Example 10> Preparation of N-Acetyl-γ-Glutammylalanine

N-Acetyl-γ-glutammylalanine was synthesized by Genescript (USA). The MSdata of this compound are shown in FIG. 9 .

<Example 11> Evaluation of Skin-Soothing Effect and Severity of AtopicDermatitis for Acyl Derivatives of Tryptophan and Acyl Derivatives ofAlanine

Skin-soothing effect and the severity of dermatitis were evaluated forthe acyl derivatives of tryptophan synthesized in Example 9, the acylderivative of alanine synthesized in Example 10 and N-palmitoylalanine(purchased from Santacruz (USA)) according to the method of Example 4(Table 2)

TABLE 2 Mouse 1 Mouse 2 Ery- Ede- Es- Dry- Abra- Licheni- Ery- Ede- Es-Dry- Abra- Licheni- thema ma char ness sion fication Sum thema ma charness sion fication Sum Control 0 0 0 0 0 0 0 0 0 0 0 0 0 0 DNFB 2 3 3 42 3 17 4 3 3 4 3 3 20 (D) D + 2 2 2 2 2 2 12 2 2 2 3 2 2 13 N-propionylL-tryptophan D + 1 2 2 2 1 2 10 2 1 1 2 2 2 10 N-butyryl L-tryptophanD + 2 2 2 2 1 2 11 2 2 1 2 1 2 10 N-pentanoyl L-tryptophan D + 1 2 1 1 22 9 2 1 2 1 2 2 10 N-undecanoyl L-tryptophan D + 1 2 1 1 1 2 6 2 1 2 2 21 10 N-palmitoyl- L-tryptophan D + 1 1 1 1 1 0 5 1 1 2 2 1 0 7 N-(Z)-docos-13- enoyl L-tryptophan D + 2 2 2 2 2 2 12 2 2 1 2 2 1 10N-stearyl-L- tryptophan D + 2 1 2 2 2 3 12 1 1 1 2 2 3 10 N-oleoyl-L-tryptophan D + 1 2 1 1 1 1 7 2 1 1 1 1 1 7 N-palmitoyl L-alanine D + 0 10 0 1 2 4 1 1 2 1 1 2 8 N-acetyl y-glutammyl- L-alanine Mouse 3 Ery-Ede- Es- Dry- Abra- Licheni- Devia- thema ma char ness sion fication SumMean tion Control 0 0 0 0 0 0 0 0 0 DNFB 3 3 3 3 3 3 15 17.3 2.0 (D) D +2 1 2 1 2 1 9 11.3 1.7 N-propionyl L-tryptophan D + 1 1 1 1 1 2 6 8.71.9 N-butyryl L-tryptophan D + 2 2 2 1 2 1 10 10.3 0.5 N-pentanoylL-tryptophan D + 1 2 2 1 1 2 9 9.3 0.5 N-undecanoyl L-tryptophan D + 2 21 2 1 2 10 8.7 1.9 N-palmitoyl- L-tryptophan D + 2 1 2 2 1 1 9 7 1.6N-(Z)- docos-13- enoyl L-tryptophan D + 2 2 2 1 2 2 11 11 0.8N-stearyl-L- tryptophan D + 2 1 1 2 2 2 10 10.7 0.9 N-oleoyl-L-tryptophan D + 2 1 1 2 2 1 9 6.7 0.5 N-palmitoyl L-alanine D + 1 1 1 0 12 6 6 2 N-acetyl y-glutammyl- L-alanine

As seen from Table 2 and FIG. 8 , N-acyl-L-tryptophan andN-acyl-L-alanine showed significant skin-soothing and atopicdermatitis-treating effects.

While the exemplary embodiments have been shown and described, it willbe understood by those skilled in the art that various changes in formand details may be made thereto without departing from the spirit andscope of this disclosure as defined by the appended claims.

(Project ID) 2017R1A2A1A17069822 (Ministry in Charge) Ministry ofScience and ICT (Research Management Agency) National ResearchFoundation of Korea (Research Project Title) Support of Follow-up Studyof Leading Research Project

(Research Title) Development of leukotriene derivative-based candidatematerials for treatment of atopic dermatitis

(Contribution Rate) ½ (Research Institute) Jeonbuk National University(Research Period) 2017 Nov. 1-2019 Feb. 28 (Project ID) 2017R1A5A2015061(Ministry in Charge) Ministry of Science and ICT (Research ManagementAgency) National Research Foundation of Korea (Research Project Title)Leading Research Center Support Project

(Research Title) Research on metabolic inflammation

(Contribution Rate) ½ (Research Institute) Jeonbuk National University(Research Period) 2017 Nov. 1-2019 Feb. 28

1. A method for preventing or treating pruritus, comprisingadministering a composition to a subject in need thereof, wherein saidcomposition comprises an N-acylamino acid selected from the groupconsisting of N-acetylalanine, N-acetylthreonine, N-acetylarginine,N-acetyltryptophan, N-propionyltryptophan, N-butyryltryptophan,N-pentanoyltryptophan, N-undecanoyltryptophan, N-palmitoyltryptophan,N-docos-13-enoyltryptophan, N-stearyltryptophan, N-oleoyltryptophan,N-acetyl-γ-glutammylalanine and N-palmitoylalanine; or apharmaceutically acceptable salt thereof as an active ingredient.
 2. Themethod according to claim 1, wherein the N-acylamino acid is one or moreamino acid selected from the group consisting of N-acetylalanine,N-acetylthreonine, N-acetylarginine and N-acetyltryptophan.
 3. Themethod according to claim 2, wherein the N-acylamino acid is selectedfrom the group consisting of N-acetyl-L-alanine, N-acetyl-L-threonine,N-acetyl-L-arginine and N-acetyl-L-tryptophan.
 4. The method accordingto claim 1, wherein the N-acylamino acid is selected from the groupconsisting of N-propionyl-L-tryptophan, N-butyryl-L-tryptophan,N-pentanoyl-L-tryptophan, N-undecanoyl-L-tryptophan,N-palmitoyl-L-tryptophan, N-docos-13-enoyl-L-tryptophan,N-stearyl-L-tryptophan, N-oleoyl-L-tryptophan,N-acetyl-γ-glutammyl-L-alanine and N-palmitoyl-L-alanine.
 5. The methodaccording to claim 1, wherein the pruritus is selected from the groupconsisting of vulvar pruritus, vaginal pruritus, paroxysmal pruritus,winter pruritus, anal pruritus, scrotal pruritus, aquagenic pruritus,scalp pruritus, nasal pruritus, oral pruritus and ocular pruritus. 6.The method according to claim 1, wherein the composition is preparedinto a formulation selected from the group consisting of a formulationfor external application to skin, an aerosol, a spray, a collyrium, anoral medication and an injection.